Developmental Reprograming of Metabolism and Behavior by Environmental Endocrine Disruptors

Environmental endocrine disruptors (EEDs) are chemicals that may interfere with the body’s endocrine system and produce adverse effects in both humans and wildlife. Exposure to these substances during critical periods of prenatal or neonatal life may cause permanent reprogramming of target tissues which often do not present immediate phenotypes but can ultimately lead to adulthood onset diseases. The growing evidence indicates that underlying molecular mechanisms of this reprograming include long-term changes in chromatin structure and accessibility for transcription machinery (changes in epigenome). My main research interests consist in the study of long-term reprogramming of metabolic and neuro-behavioral functions by EEDs in mammal models using a variety of approaches including state of the art genomic and epigenetic methods which capitalize on recent advances in high throughput sequencing.

Metabolic reprogramming -The prevalence of obesity and type 2 diabetes has risen dramatically in children in the United States over the past few decades according to NIH reports. More than 60% of children 10 years and older either are or will become obese later in life and one in four overweight children has impaired glucose tolerance. An emerging hypothesis links obesity and metabolic diseases epidemic with chemical exposures during vulnerable windows of in utero and early life development. We hypothesize that in utero and early life exposure to persistent bioaccumulative brominated flame retardants (BFRs), may permanently reprogram metabolism in liver and ultimately cause the development of adult metabolic disease. We use in vivo mouse model to verify this hypothesis through the analysis of long lasting changes in gene expression, chromatin accessibility, and histone modifications in response to developmental exposure to environmentally prevalent BFRs at environmentally relevant doses. Also we plan to analyse the role of altered endocrine control by hypothalamo-pituitary axis in maintaining long-term changes in liver gene expression.

Neuro-behavioral reprogramming - It is shown in numerous studies that neural development is the most sensitive endpoint affected by EEDs following in utero and early life exposures. We hypothesize that with global scale of environmental exposures, behaviour of every human being is altered from its norm, although these changes stay mostly unnoticed, and only the most vulnerable part of population develops clinical signs of altered behaviour in a form of ADHD, autism spectrum disorders and other disorders. We hypothesize further that the less affected majority may still have behavior altered to some degree. These subtle changes in behavior of each member of a population may result in marked changes at the next level of organization of biological systems – at the level of communities and ecosystems. We plan to verify these hypotheses in experiments with laboratory rodents in which at current step we focus on the analysis of long-term changes in social behavior and underlying changes in transcriptome and epigenome in different brain structures after developmental exposures to BFRs.